Initially employed for in-depth examination of cell development1, stem cells have become a cornerstone for regenerative medicine, including cell-based therapies for treatment of neurological disorders2,3. Stem cells exist even in adulthood8, and possess the capacity to self-renew and differentiate into multiple lineages9, contribute to normal homeostasis10, and exert therapeutic benefits either endogenously11-14 or following transplantation in injured organs, i.e., brain15-21. The subventricular zone (SVZ) of the lateral ventricles and the sub granular zone of the hippocampus dentate gyrus are the two major stem-cell niches in the adult brain22,23, although quiescent neural stem cells (NSCs) have been detected in other brain regions24. Induction of endogenous stem cells after injury would provide new opportunities in regenerative medicine2,3,11-21.
Cells other than pluripotent stem cells have also been used in the treatment of disorders of the central nervous system. As one example, SB623 cells (which are cells derived from marrow adherent stem cells in which an exogenous Notch intracellular domain has been expressed) are used for the treatment of stroke, by transplantation at or near the site of ischemic insult. See, for example, U.S. Pat. No. 8,092,792 and Yasuhara et al. (2009) Stem Cells Devel. 18:1501-1513. U.S. Pat. No. 7,682,825 describes additional uses of SB623 cells in the treatment of a number of disorders of the central and peripheral nervous systems.
Despite these scientific advances and some initial clinical studies25-27, a fundamental gap in our understanding of cell therapy is a knowledge of the mechanisms by which transplanted cells facilitate the repair of damaged neural tissue. To date, increased graft survival and graft persistence have been considered the crux of successful cell transplantation therapy in affording therapeutic benefits in hematologic and non-hematologic disorders. Thus, much effort has been directed to prolonging the survival and persistence of transplanted cells. Accordingly, methods for effective cell therapy, that do not require the persistence of large amounts of transplanted cells, would be advantageous.
Traumatic brain injury (TBI) refers to damage to the brain resulting from external mechanical force. TBI can result from falls, firearm wounds, sports accidents, construction accidents and vehicle accidents, among other causes. Victims of TBI can suffer from a number of physical, cognitive, social, emotional and/or behavioral disorders.
Little can be done to reverse the initial physical damage of a TBI. Therefore, treatment options consist primarily of stabilization to prevent further damage in the acute phase, and rehabilitation thereafter. Because of these limited options, additional methods and compositions for treatment of TBI are needed.